Lymphatic vessels in and around tumors are a key determinant in lymphatic metastasis. This study will provide tools for systemic delivery of tumor treatments through the lymphatic route. Peptide library-based vascular targeting, developed in the applicant's laboratory, will be used to profile molecular alterations in the lymphatic vasculature during tumorigenesis. Peptides that specifically recognize the lymphatics in a number of tumor types and stages of tumor development will be isolated. The design of the screening will favor peptides that recognize the lymphatics in a range of tumors, rather than being selective for an individual tumor model. The specificity of these and already existing lymphatic homing peptides will be ascertained by testing peptide binding to normal and cancerous tissues from mice and from human patients. The target molecules ('receptors') for the most promising peptides will be identified, and antibodies will be prepared against the receptors. The peptides identified and characterized as described above, and antibodies prepared against their receptors, will be tested for their effects on lymphatic vessels and tumor growth, and their ability to deliver peptide-drug or antibody drug conjugates to pre-malignant and malignant lesions. This approach specifically targets the treatments to areas that may not be readily accessible through the blood circulation. Destroying the lymphatic vessels in and around the tumor along with the adjacent tumor cells may be particularly effective in reducing lymphatic metastasis. Promising compounds emerging from these experiments will be tested in pre-clinical cancer models for treatment of cancer and prevention of metastasis. [unreadable] [unreadable]